Submit Your Article CMED MEACR meeting
An official publication of the Middle-Eastern Association for Cancer Research
Clinical Cancer Investigation Journal
ISSN Print: 2278-1668, Online: 2278-0513
ARTICLE
Year: 2014   |   Volume: 3   |   Issue: 6   |   Page: 472-477     View issue
Role of lectins in clinical settings
Charu Kapoor, Sharad Vaidya, Harpreet Kaur, Ajay Jain

Lectins are a diverse class of proteins derived from either plants, microbial or animal sources and may be soluble or membrane bound. It is a tetramer made up of four nearly identical subunits. In humans, lectins have been reported to cause digestive distress, carbohydrate, and other disorders. This review intends to put forward basic foundation in carbohydrate structure and function, lectin biology and the implications of glycobiology in human health and disease, particularly in cancer therapeutics. These topics are among the hundreds included in the field of glycobiology and form the cornerstone of glycobiology.

Applications, biological significance, lectins, structure

INTRODUCTION

It is difficult to discuss carbohydrates without reference to lectins. The term lectin is derived from the Latin word "legere" meaning "to bind" or "to pick." Lectins are defined as proteins that preferentially recognize and bind carbohydrate complexes protruding from glycolipids and glycoproteins [1] Lectins are abundant in nature, and were first isolated in 1888 by Stillmark at Estonia University. [2] Lectins are found in most plants but are particularly high in legumes and grains [3],[4] Seafood such as shellfish, eel, halibut, and flounder also have high lectin contents. The amount of lectin concentration generally accounts for 1-3% of the protein content of the specific food, and in the case of plants, the amount is dependent upon the degree of plant maturation. [2]

Lectins are nonimmunologic protein-polysaccharide molecules having a strong binding affinity for the complex carbohydrates, which are abundant on cell surfaces. [3] Lectins bind in a manner similar to antibodies, forming an irreversible covalent bond. The binding of lectins can often be inhibited by specific monosaccharides. [3],[4],[5] An example of a high molecular weight polysaccharide, which conveys a protective effect is arabinogalactan, found in a variety of foods and herbal medicines. This class of molecules has been shown to occupy the binding sites of various microorganisms, preventing them from attaching to cellular surfaces and making it easier for the immune system to eliminate them. [4]

The aim of this review is to highlight instructionally useful discussion on structure and function of lectins and their role in human health and disease, particularly in cancer, metastasis and its therapeutics.

Back to History

The beginnings of lectinology date back to 1888 when Herrmann Stillmark described the agglutination properties of ricin; however, the modern age of lectinology started nearly 100 years later (Bies, 2004; Sharon and Lis, 2004). Lectins were initially found and described in plants, but in subsequent years multiple lectins were isolated from microorganisms and also from animals (Sharon and Lis, 2004). During the past several years, however, many primary and three-dimensional structures of lectins have been elucidated. Structural studies conducted on animal lectins suggested that the carbohydrate binding activity of most lectins was generated by limited amino acid residues designated as the carbohydrate recognition domain (CRD) (Sharon and Lis, 2004) [Table 1].

Until recently, most work on the medical significance of lectins has focused on their role as causes of disease or as immune system modulators. [4],[5],[6] In the 1950s, 1960s, and early 1970s, specific investigations of their role in causing certain diseases were undertaken by a variety of authors. [7],[8],[9],[10] Most investigations of lectins have been primarily focused on their diagnostic role as markers of specific disease states, but some later studies [11] have begun to look at their potential as therapeutic agents.{Table 1}

STRUCTURE OF LECTINS

According to Goldstein et al., lectins are mainly made up of carbohydrate binding proteins or glycoproteins of nonimmune origin, which binds the cell or precipitates, glyco-conjugates. The specific capacity of lectins to bind with the cell surface mainly depends on the monosaccharide or simple oligosaccharides [Figure 1]. [7],[8],[9],[10]{Figure 1}

Some lectins structurally differentiated as: [1],[2],[3]

Erythrine C lectinsConcavalin C lectinsUlex europeus lectinsC-type lectins (CTLs).

Lectins are classified into four groups, based on their affinity to bind with:

GlucoseGalactose and N-acetyl-D-galactosamineL-fucoseSialic acids.

Another classification of lectins based on lectin-like protein is [Figure 2] and [Figure 3]:

Type I: Depending upon structural and evolutionary sequence similarities. Includes - beta prism lectin (B-type), calcium dependent lectins (C-type), fibrinogen/collagen domain containing lectins (F-type), garlic and snow drop lectins (G-type), hylauronic bonding protein (H-type), immunoglobulin superfamily lectins (I-type), alpha mannosaccaridase-related lectin (M-type), nucleotide phosphohydrolases (N-type), racin lectin (R-type), tachupleus tridentatus (T-type), wheat germ agglutinin (W-type), xanopus egg lectin (X-type)Type II: Depending upon proteins without established evolutionary. Includes: Annexins, pentraxins, G-domains, CD11b/CD 18 (beta integrins, CR3).{Figure 2}{Figure 3}

Lectin families

Within the animal lectins, several highly conserved CRD amino acid sequences have been identified, thus allowing investigators to categorize the majority of these lectins into structurally related families and superfamilies (Sharon and Lis, 2004). CTLs are the most abundant of all animal lectins, and the CTL superfamily is grouped into three families: Selectins, collectins, and endocytic lectins (Sharon and Lis, 2004) [1] [Figure 2],[Figure 3] and [Figure 4].{Figure 4}

Structure of lectins

The binding of lectins is: [7]

ReversibleNoncovalentSurface containing conjugate acts as lectin recertorSpecificity: Based on hapten inhibition testAll lectin molecules possess: Two/more carbohydrate binding sites (essential for agglutination).

Properties

Most of the plant and animal lectins are resistant to both heating and digestion.Many of these lectins are highly stable, thermally (at 70°C for > 30 min), but these lectins do not completely degrade with cooking. Some of them are relatively resistant to digestive enzymes and acidsSome lectins are degraded and others pass through gut, about 1-5% are re-absorbed into the blood stream in animals, which sufficient to cause an immune response. [7]

Biological significance of lectins

The biological role of lectins is based on conjecture rather than knowledge. The question of the possible physiological role of lectins has intrigued investigators from the beginning. [8] Due to their proprietory role in adhesion and agglutination, lectins have been considered as important in both symbiotic and pathogenic interaction between some microorganisms and hosts. The microbial lectins may play a role in adhesion. [7]

Lectins serve as means of attachment of different kinds of cells as well as of viruses to other cells via the surface carbohydrates of the cells to be attached. In some cases, cell surface lectins bind to particular glycoproteins, whereas in other cases the carbohydrates of cell surface glycoproteins or glycolipids serve as sites of attachment for biologically active molecules that have specificity towards carbohydrate, for example, microorganisms, various plant toxins, galactic etc., as shown in [Figure 5]. [8]{Figure 5}

Endogenous lectins mediate biological processes such as [Figure 5]:

Cell-cell self-recognitionCell-extracellular matrix interactionsGamete fertilizationEmbryonic developmentCell growth, cell differentiationCell signalingCell adhesion and migrationApoptosisImmunomodulation and inflammationHost-pathogen interactionsGlycoprotein folding and routingMitogenic induction andHomeostasis.

[INLINE:1]

APPLICATIONS

Lectins have varied role in human

In carcinoma and metastasisOdontogenic cysts and tumorsMicrobiologyFood and human reactionInflammation [7]Use in medicine and medicine researchUse as a biochemical toolLectins - toxins or therapeutics.

In dysplasia

Malignant tumors of the oral cavity represent a major public health concern, especially in view of the increasing incidence and prevalence rates observed along the last few years1. Parkin et al. (1999) estimated about 210,000 new cases per year worldwide. Some studies have shown that the process of malignancy is associated with a variety of changes in cell surface carbohydrate expression, not to mention the role played by carbohydrates in determining the metastatic capabilities of neoplastic cells. [4],[5],[6],[7],[8] Few studies have suggested that membrane bound carbohydrates may be essential for cellular differentiation and malignant transformation. In epithelium, lectins are detected on the basal cells and spinous cells. This sequential distribution of lectins was observed to be more disturbed with increasing grade of epithelial dysplasia. [7] Nangia-Makker et al. (2002) had reported that developing cancer cells use the functional groups of carbohydrate molecules to avoid being recognized by immune cells. [9] During metastasis formation, carbohydrates are involved in interactions between tumor cells, between tumor cells and the extracellular membrane, or between tumor cells and endothelial cells. [4] However, due to the structural complexity of carbohydrates and the scarce knowledge currently available in the field of glycobiology, a better understanding of this mechanism is not yet possible. [6],[9],[10]

Lectins in tumor markers

These are polyvalent proteins of nonimmune origin. Glycoproteins and glycolipids are the proteins present on the cell surface of squamous cells, which acts as antigens. These markers help in immunohistochemical (IHC) studies on skin or oral mucosa of human tissue. [7]

Role of lectin in oral cancer and metastasis

Squamous cell carcinomas (SCCs) of the oral cavity are the most common cancers among men and the third most common among women. [1] Nearly, half of them have lymph node (LN) metastasis at the time of diagnosis and half the remaining develop LN disease later on. Among the various factors that influence prognosis, LN involvement is probably the most important one. The size of the primary tumor, invasion of muscle or bone, and histological grade influence the development of LN metastasis. Large tumors have higher frequency of LN metastasis, and tumors with skin or bone involvement have higher chance of node involvement; but, not infrequently, small tumors with no apparent deep invasion develop LN metastasis. Verrucous carcinomas are known to produce LN metastasis rarely, whereas it is very common for poorly differentiated SCCs. However, at present, there are no methods which can identify the invasive and metastatic potential of oral cancers. It has been suggested that the cell membrane is involved when a malignant cell shifts from a state of local growth to metastatic growth. [8],[9],[10],[11],[12] Tumor metastasis and invasion may be mediated by carbohydrates on the surfaces of these cells. Alterations in the cell surface carbohydrates have been found to severely affect the metastatic potential of experimental tumors. [12],[13],[14],[15],[16],[17],[18] Plant lectins, because of their specific carbohydrate binding properties, have been used extensively as probes to study the surface architecture of normal and transformed cells. Differences in cell surface carbohydrate expression can be detected using lectins and such differences have been shown to be of prognostic significance. [18],[19],[20],[21],[22],[23]

Nangia-Makker et al. (2002) reported that developing cancer cells use the functional groups of carbohydrate molecules to avoid being recognized by immune cells. During metastasis formation, carbohydrates are involved in interactions between tumor cells, between tumor cells and the extracellular membrane, or between tumor cells and endothelial cells. However, due to the structural complexity of carbohydrates and the scarce knowledge currently available in the field of glycobiology, a better understanding of this mechanism is not yet possible. Among animal lectins, galectins stand out because they have a permanent sequence of about 130 amino acids for the recognition of carbohydrates, in addition to a high affinity for beta-galactosides present in both normal and tumor cells. As a result of this lectin-cell interaction property, galectins are involved in several biological processes, such as cell cycle control, immune response, cell adhesion, apoptosis, and metastasis. [23],[24],[25]

Galectin 3 can present both nuclear and cytoplasmic IHC staining. Cytoplasmic staining is associated with the antiapoptotic function of this lectin, thus promoting tumor progression; however, when expressed in the nucleus, the apoptotic function of Galectin 3 is lost. Gillenwater et al. analysed the expression of Galectins 1 and 3 in 35 cases of primary SCC of the head and neck and found that Galectin 1 was usually expressed in the basal layer of adjacent normal tissue, stroma and at the periphery of invasive tumor islands. Galectin 3, in turn, was found in superficial mucosal layers and adjacent to keratin pearls in areas of invasion. The authors concluded that galectins are expressed in the tumor cell surface, where they may participate in cellular interactions, and that the expression pattern of galectins appears to be associated with tumor grade, suggesting a role of galectins as biological markers in SCCs of the head and neck. [23],[24],[25],[26],[27],[28]

The risk of LN metastasis is of prime consideration in deciding the treatment policy for an oral cancer patient presenting with clinically negative neck. If there is low risk of LN metastasis localized treatment like excision or brachytherapy can be opted for, whereas a patient with a high risk needs prohylactic neck dissection or irradiation. A clinician usually relies on various clinico-pathological factors like histological subtype, primary tumor size and presence of local invasion for this, considering them as "tests". [29],[30],[31],[32],[33],[34],[35] Understandably both sensitivity and specificity of the test are important here since it is important to avoid unnecessary treatment and yet not miss out treatment for those whom it is necessary. Tumor metastasis and invasion may be mediated by carbohydrates on the surfaces of these cells. A direct correlation between sialylation and metastatic capacity has been observed in several tumor cell lines. [29],[30],[31],[32],[33],[34],[35],[36] Alterations in the cell surface carbohydrates have been found to severely affect the metastatic potential of experimental tumors. Specific glycosylation defects are known to result in loss of metastatic potential. The involvement of carbohydrates in metastasis formation would imply that tumor cells with different metastatic potential possess distinct qualitative or quantitative differences in their glycosylation of membrane glycoconjugates. [30] A correlation between the amount of cell surface sialic acid and metastatic potential was found by Yogeswaran et al. Relation of Ulex europaeus agglutinin (UEA-1) binding to disease-free interval and survival in breast cancer was reported by Fenlon et al. [28]

To sum-up we can suggest that cell membrane characteristics, particularly the density of sugar residues is of importance in determining LN metastatic potential of oral cancers. The prediction of LN metastasis can be made more accurately if lectin binding characteristics are taken into consideration along with the usual clinical and histological parameters. There is a need for further research in this area, particularly with regard to the role of immune responses, lectin binding pattern and cell membrane characteristics. [37],[38],[39]

CONCLUSION

Role of lectin in research is on steady rise based on their ability to bind with specific glucoconjugates. Although lectins have been marketed as potential toxins, there is now extensive literature reporting the activity of lectins in a number of different tissues and processes. Lectins are unique and naturally occurring cytochemical and histochemical tool, which in near future will further emphasize their values as potential diagnostic reagents for the clinicians. A relatively high number of studies have been conducted to investigate the role of lectins as biomarkers of oral cavity tumors, covering a variety of lesions and lectins. In our review, studies assessing SCCs and peanut agglutinin and UEA-1 lectins were the most frequent ones, as well as studies focusing on one specific lectin and one lesion. Further analyses of lectins as biomarkers should be undertaken to improve our understanding of the processes involved in malignant tumor formation.

References

Goldstein IJ, Hughes RC, Monsigny M, Osawa T, Sharon N. What should be called a lectin? Nature 1980;285:66.

D′Adamo P. Gut Ecosystem Dynamics II, Special Characteristics: Lectins and Mitogens Monograph 1989.

Sharon N, Lis H. Lectins - Proteins with a sweet tooth: Functions in cell recognition. Essays Biochem 1995;30:59-75.

Freed D. Lectins in food: Their importance in health and disease. J Nutr Med 1991;2:45-64.

Moreira Rde A, Ainouz IL, De Oliveira JT, Cavada BS. Plant lectins, chemical and biological aspects. Mem Inst Oswaldo Cruz 1991;86 Suppl 2:211-8.

Sharon N, Lis H. History of lectins: From hemagglutinins to biological recognition molecules. Glycobiology 2004;14:53R-62.

Springer GF, Desai PR. Monosaccharides as specific precipitinogens of eel anti-human blood-group H (O) antibody. Biochemistry 1971;10:3749-61.

Goldstein IJ, Hayes CE. The lectins: Carbohydrate-binding proteins of plants and animals. Adv Carbohydr Chem Biochem 1978;35:127-340.

Watkins WM, Morgan WT. Neutralization of the anti-H agglutinin in eel serum by simple sugars. Nature 1952;169:825-6.

Drickamer K. Two distinct classes of carbohydrate-recognition domains in animal lectins. J Biol Chem 1988;263:9557-60.

Lis H, Sharon N. Application of lectins. Springer Science and Business Media, 2003; p. 293-370.

Lis H, Sharon N. Lectins as molecules and as tools. Annu Rev Biochem 1986;55:35-67.

Alroy J, Orgad U, Ucci AA, Pereira ME. Identification of glycoprotein storage diseases by lectins: A new diagnostic method. J Histochem Cytochem 1984;32:1280-4.

Sharon N, Lis H. Lectins as cell recognition molecules. Science 1989;246:227-34.

Mody R, Joshi S, Chaney W. Use of lectins as diagnostic and therapeutic tools for cancer. J Pharmacol Toxicol Methods 1995;33:1-10.

Lord JM. The use of cytotoxic plant lectins in cancer therapy. Plant Physiol 1987;85:1-3.

Komath SS, Kavitha M, Swamy MJ. Beyond carbohydrate binding: New directions in plant lectin research. Org Biomol Chem 2006 21;4:973-88.

Damjanov I. Biological diseases. Lectin Biochemistry. Lab Invest 1987;57:5-20.

Agrawal BB, Goldstein IJ. Specific binding of concanavalin A to cross-linked dextran gels. Biochem J 1965;96:23contd-5c.

Lis H, Sharon N.Lectins as molecules and tools. Annu Rev Biochem 1989;55:35-67.

Etzler ME, Branstrator ML. Differential localization of cell surface and secretory components in rat intestinal epithelium by use of lectins. J Cell Biol 1974;62:329-43.

Nair MK, Sankaranarayanan R, Padmanabhan TK, Padmakumari G. Clinical profile of 2007 oral cancers in Kerala, India. Ann Dent 1988;47:23-6.

Irimura T, Nicolson GL. Carbohydrate chain analysis by lectin binding to electrophoretically separated glycoproteins from minute B16 melanoma sublines of various metastatic properties. Cancer 1984;44:791-6.

Steck PA, Nicolson GL. Cell surface glycoproteins of 13762NF mammary adenocarcinoma clones of differing metastatic potentials. Exp Cell Res 1983;147:255-67.

Fukutomi T, Itabashi M, Tsugane S, Yamamoto H, Nanasawa T, Hirota T. Prognostic contributions of Helix pomatia and carcinoembryonic antigen staining using histochemical techniques in breast carcinomas. Jpn J Clin Oncol 1989;19:127-34.

Leathem A, Dokal I, Atkins. N. Carbohydrate expression in breast cancer as an early indicator of metastatic potential. J Pathol 1984;142: 45

Leathem A, Atkins N, Eisen T. Breast cancer metastasis, survival and carbohydrate expression associated with lectin binding. J Pathol 1985;145:734-8.

Leathem AJ, Brooks SA. Predictive value of lectin binding on breast-cancer recurrence and survival. Lancet 1987;1:1054-6.

Fukumori T, Kanayama HO, Raz A. The role of galectin-3 in cancer drug resistance. Drug Resist Updat 2007;10:101-8. 24.

Takenaka Y, Fukumori T, Raz A. Galectin-3 and metastasis. Glycoconj J 2004;19:543-9.

Gillenwater A, Xu XC, Estrov Y, Sacks PG, Lotan D, Lotan R. Modulation of galectin-1 content in human head and neck squamous carcinoma cells by sodium butyrate. Int J Cancer 1998;75:217-24.

Dennis JW, Laferte S. Tumor cell surface carbohydrate and the metastatic phenotype. Cancer Metastasis Rev 1987;5:185-204.

Altevogt P, Fogel M, Cheingsong-Popov R, Dennis J, Robinson P, Schirrmacher V. Different patterns of lectin binding and cell surface sialylation detected on related high- and low-metastatic tumor lines. Cancer Res 1983;43:5138-44.

Yogeeswaran G, Sebastian H, Stein BS. Cell surface sialylation of glycoproteins and glycosphingolipids in cultured metastatic variant RNA-virus transformed non-producer BALB/c 3T3 cell lines. Int J Cancer 1979;24:193-202.

Yogeeswaran G, Salk PL. Metastatic potential is positively correlated with cell surface sialylation of cultured murine tumor cell lines. Science 1981;212:1514-6.

Fenlon S, Ellis IO, Bell J, Todd JH, Elston CW, Blamey RW. Helix pomatia and Ulex europeus lectin binding in human breast carcinoma. J Pathol 1987;152:169-76.

Alam SM, Whitford P, Cushley W, George WD, Campbell AM. Flow cytometric analysis of cell surface carbohydrates in metastatic human breast cancer. Br J Cancer 1990;62:238-42.

Brooks SA, Leathem AJ. Prediction of lymphnode involvement in breast cancer by detection of altered glycosylation in the primary tumour. Lancet 1991;339:71-4.

Noguchi M, Thomas M, Kitagawa H, Kinoshita K, Ohta N, Nagamori M, et al. Further analysis of predictive value of Helix pomatia lectin binding to primary breast cancer for axillary and internal mammary lymph node metastases. Br J Cancer 1993;67:1368-71.

© Clinical Cancer Investigation Journal
Online since 01 December, 2011
Creative Commons License 
ISSN Print: 2278-1668, Online: 2278-0513